The present invention provides a system and method for predicting the operation of existing and proposed networks of biochemical mechanisms, such as combinations of genetic sequences and biochemical mechanisms. In particular, a genetic sequence, or a combination of genetic sequences and other biochemical mechanisms can be modeled, using the present invention, as a set of interacting objects that operate as a biochemical circuit.
In this document the terms circuit, network and regulatory network shall be used interchangeably.
As will be explained below, biochemical networks or circuits can be modeled and simulated using bio-logic components in a manner that is analogous to the modeling of electrical circuits by electrical logic circuit components. Analysis of biochemical circuits using the present invention focuses on simulation at the "circuit logic" level.
Various types of biochemical mechanisms can be modeled at greater and lesser levels of biochemical detail by using different object models to simulate the operation of those mechanisms. In this way, simulations of biochemical circuits can be executed so as to focus on the signals (i.e., changing concentrations of molecules and chemicals that convey information) and accuracy levels of interest to the user.
By casting "bio-logic" networks in the framework of conventional switching circuits, we gain access to an enormous heritage of analysis and modeling techniques. In particular, switching circuit analysis techniques developed in the domain of electrical engineering are effective for analyzing some genetic circuits and may provide insights that are not as apparent from the biochemical perspective. One example is the central role that time delay and memory mechanisms play in determining the behavior of genetic control networks.
Intuitive analysis of large genetic regulator networks with positive and negative feedback loops is difficult. The simulation models of the present invention allow such analysis and make it possible to analyze altered genetic networks to predict mutant behavior. Furthermore, configuring well-characterized biological "components", such as those in the bacteriophage lambda genetic network, into new circuit configurations may provide access to new pharmacological strategies.
It is therefore a primary goal of the present invention to facilitate the analysis and network level design of biochemical circuits that comprise 10's to 100's of genes that control cellular events spanning minutes to hours.
Another goal of the present invention is to provide a set of reusable biochemical circuit simulation tools that can be easily rearranged to simulate the operation of a large variety of biochemical regulatory networks.
While borrowing from the circuit simulation techniques used in electrical engineering, the preferred embodiment of the present invention also simulates the stochastic fluctuations associated with biochemical regulatory signals. Stochastic fluctuations play an important role in biochemical networks. For instance, phenotypic diversity observed among individual cells within genetically uniform populations grown under identical conditions suggests that gene expression has a strong stochastic element. Through the use of various feedback mechanisms, genetic mechanisms can exhibit simultaneous stochastic gene expression and stable outcomes. However, even protein levels stabilized by autoregulatory feedback are found to have significant levels of random fluctuations. It is therefore a goal of the present invention to simulate the effect of stochastic fluctuations on biochemical networks in individual cells and to estimate the variation in network functioning and timing or phenotype distribution expected in a cell population.